The emerging pharmacology and function of GPR35 in the nervous system

• Published in: Neuropharmacology Vol. 113; no. Pt B; pp. 661 - 671
• Main Authors: Mackenzie, Amanda E., Milligan, Graeme
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2017
• Subjects: Animals; Central Nervous System - drug effects; Central Nervous System - metabolism; CNS; GPR35; Humans; Kynurenic acid; Pain; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Synaptic transmission; Zaprinast; RET; AMPA; GPR35; AHO; CNS; cGMP; Zaprinast; TRPV1; PKG; PDE; Pain; SNP; Synaptic transmission; DRG; NMDA; EC50; GPCR; Kynurenic acid
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.07.035

G protein-coupled receptor 35 (GPR35) is an orphan G protein-coupled receptor (GPCR) that can be activated by kynurenic acid at high micromolar concentrations. A previously unappreciated mechanism of action of GPR35 has emerged as a Gαi/o-coupled inhibitor of synaptic transmission, a finding that has significant implications for the accepted role of kynurenic acid as a broad-spectrum antagonist of the NMDA, AMPA/kainite and α7 nicotinic receptors. In conjunction with previous findings that link agonism of GPR35 with significant reduction in nociceptive pain, GPR35 has emerged as a potential effector of regulation of mechanical sensitivity and analgesia of the Ret tyrosine kinase, and as a receptor involved in the transmission of anti-inflammatory effects of aspirin- potentially through affecting leucocyte rolling, adhesion and extravasation. Single nucleotide polymorphisms of GPR35 have linked this receptor to coronary artery calcification, inflammatory bowel disease and primary sclerosing cholangitis, while chromosomal aberrations of the 2q37.3 locus and altered copy number of GPR35 have been linked with autism, Albight's hereditary osteodystrophy-like syndrome, and congenital malformations, respectively. Herein, we present an update on both the pharmacology and potential function of GPR35, particularly pertaining to the nervous system. This review forms part of a special edition focussing on the role of lipid-sensing GPCRs in the nervous system.
This article is part of the Special Issue entitled ‘Lipid Sensing G Protein-Coupled Receptors in the CNS’.
•GPR35 is a poorly characterized G protein-coupled receptor.•GPR35 is suggested to be a target for kynurenic acid.•Suggestions that GPR35 might be activated by lysophosphatidic acid remain unvalidated.•Suggestions that this receptor is activated by CXCL17 require confirmation.•Roles in the CNS include pain modulation in dorsal root ganglia.